Insulin-Dependent Regulation of Insulin Receptor Concentrations: A Direct Demonstration in Cell Culture

Gavin, James R.; Roth, Jesse; Neville, David M.; Meyts, Pierre De; Buell, Donald N.

doi:10.1073/pnas.71.1.84

Cited by 945 publications

(383 citation statements)

References 33 publications

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“…Homologous insulin receptor up-regulation, as a result of decreased ambient insulin concentration, is the likely mechanism accounting for increased insulin receptor number in liver and kidney. This is confirmed by experiments performed in cultured cells [29,30]. With regard to the kidney, the present study demonstrates that insulin receptors are up-regulated in the renal cortex of insulin-deficient rats.…”

Section: Discussionsupporting

confidence: 76%

Effects of angiotensin II on insulin receptor binding and mRNA levels in normal and diabetic rats

et al. 1997

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The observation that hyperinsulinaemia and insulin resistance are present in subjects with essential hypertension has led to the hypothesis that insulin is involved in the pathophysiology of this disease [1][2][3]. When considering possible pathogenetic mechanisms that could mediate the prohypertensive effect of insulin, particular attention has been paid to the renal actions of the hormone. Insulin decreases urinary sodium excretion in rats [4], dogs [5,6], and humans [7, Diabetologia (1997) Summary Both the density and level of mRNA encoding insulin receptors in the kidney are inversely related to the dietary sodium content, suggesting a feedback mechanism that limits the insulin-induced sodium retention when extracellular fluid volume is expanded. Because angiotensin II affects tissue sensitivity to insulin in humans, we investigated whether angiotensin II affects insulin receptor binding and mRNA levels in the kidney, liver, and renal arteries of normal rats and rats with streptozotocin-induced diabetes mellitus. Non-diabetic and diabetic rats were infused for 7 days with either vehicle or angiotensin II at a rate of 200 ng ⋅ kg −1 ⋅ min −1 . In a separate experiment, normal rats were treated with an angiotensin converting enzyme inhibitor (captopril, 100 mg/dl in the drinking water) or vehicle for 7 days. Regional analysis of insulin receptor binding in the kidney and renal arteries was performed by an in situ technique using computerized microdensitometry and emulsion autoradiography. Insulin receptor mRNA levels were determined in renal and hepatic tissue by Northern blot hybridization and normalized with 28S rRNA. No differences in blood pressure were observed among diabetic and non-diabetic rats infused with either vehicle or angiotensin II, whereas captopril-treated rats had significantly lower blood pressure levels than their respective controls. Angiotensin II significantly decreased plasma renin concentration in both non-diabetic and diabetic rats. Insulin receptor number was significantly greater in the renal cortex of diabetic rats than in non-diabetics, whereas no significant differences were found in the outer medulla, inner medulla, or renal arteries. Angiotensin II infusion did not affect either the number or affinity of insulin receptors in any of the renal regions studied. Insulin receptor mRNA levels were significantly greater in the kidney and liver of diabetic rats than in non-diabetics and were not affected by angiotensin II infusion. Similar to angiotensin II infusion, captopril treatment did not affect either renal insulin receptor binding or mRNA levels. Thus, diabetic rats have increased insulin receptor binding and mRNA levels in comparison to non-diabetic rats. Angiotensin II infusion and captopril treatment do not affect insulin receptor binding and mRNA levels in the kidney, arguing against a role for this peptide in the modulation of renal sensitivity to insulin. [Diabetologia (1997) 40: 770-777]

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Section: Discussionsupporting

confidence: 76%

Effects of angiotensin II on insulin receptor binding and mRNA levels in normal and diabetic rats

et al. 1997

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“…In contrast, in vitro, the downregulation of IR has been demonstrated across several orders of magnitude of insulin concentration. 26 This observation therefore raises the possibility that the mechanisms of IR downregulation in vivo are more complex than those in tissue culture.…”

Section: Discussionmentioning

confidence: 95%

Muscle insulin receptor concentrations in obese patients post bariatric surgery: relationship to hyperinsulinemia

et al. 2004

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OBJECTIVE:Obesity results in insulin resistance. Bariatric surgery for obese individuals induces weight loss, improves insulin sensitivity, and lowers insulin levels. We investigated the mechanisms of this improvement. DESIGN: Insulin receptor (IR) content, IR signaling, and adiponectin levels were measured in nine morbidly obese subjects before and after bariatric surgery. SUBJECTS: Seven female and two male, average age 4472y, BMI 440 kg/m 2 and/or at least 100 lbs over ideal body weight, undergoing elective bariatric surgery. MEASUREMENTS: Before surgery BMI, fasting plasma glucose, adiponectin, and insulin levels were measured. A fasting muscle biopsy was obtained from the vastus lateralis for IR concentration and autophosphorylation activity measurements. These procedures were repeated 1 y after surgery. RESULTS: At 1 y after surgery, the subjects had lost an average of 48.375.6 kg (Po0.001), insulin sensitivity had significantly increased as determined by the minimal model (SI 0.7270.18 vs 3.8671.43, Po0.05), and IR content had increased two-fold in muscle (2.170.4 vs 4.370.7 ng/mg protein, Po0.01). The increase in IR content was related to fasting insulin levels. In the subjects with the lowest IR function, there was also an increase in IR function. Plasma adiponectin increased by 40% following weight loss (7.471.6 pre vs 10.371.3 mg/ml post, Po0.05). There was no significant change in muscle content of the IR inhibitor, PC-1. CONCLUSION: Increased IR content, most likely regulated by insulin levels, may be one contributor to the increased insulin sensitivity that occurs when morbidly obese patients undergo bariatric surgery.

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“…At least for the adipose tissue it may well be, as also suggested by Grey and Kipnis [40], that the diminished acute effect of insulin represents an adaptive phenomenon which is secondary to the hyperinsulinemia. It has indeed been shown that the presence of insulin during the culture of human lymphocytes leads to a diminished number of insulin receptors [41]. Whether a similar feedback mechanism exists for human fat cells is presently unknown but may well be the case.…”

Section: Discussionmentioning

confidence: 99%

Human adipose tissue in culture V. Studies on the metabolic effects of insulin

1976

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Summary.Specimens of human adipose tissue were cultured for one week with or without the addition of insulin. The basal as well as the noradrenaline-stimulated lipolysis were enhanced in the explants cultured with insulin, showing that the long-term effect of the hormone is lipolytic. However, an acute antilipolytic effect of insulin could be demonstrated in these explants in the subsequent short-term incubations. The basal rate of glucose incorporation into the lipids was enhanced in the explants cultured with insulin. When insulin was added in the short-term incubations these explants did not further respond to the hormone while this was the case with the explants cultured without insulin. Thus, it seems that prolonged exposure to insulin leads to a diminished acute effect of the hormone on glucose metabolism. However, the same explants responded to the antilipolytic effect showing that insulin was able to bind itself to the membrane. The activities of hexokinase (HK), glucose-6-phosphate dehydrogenase (G6PDH), pyruvate kinase (PK) and lactate dehydrogenase (LDH) were increased in large fat cells both in freshly excised tissue and in the cultured explants. However, the activity of phosphofructokinase (PFK) did not correlate with the cell size. The presence of insulin during the culture period enhanced the activities of G6PDH, PK, and LDH, while this was not found for HK or PFK. The data thus suggest that the metabolic capacity of human fat cells is enhanced by long-term exposure to insulin. Although enzyme induction could be shown for G6PDH, PK and LDH it seems unlikely that this is of importance for the increased rates of glucose metabolism in these explants since the rate-limiting enzymes, HK and PFK, were not increased. Most probably, *Part of these data were presented at the First International Congress on Obesity in London, England on 9-11 October, 1974. then, this stimulating effect of insulin is exerted on the membrane and the rate of glucose transport.

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Insulin-Dependent Regulation of Insulin Receptor Concentrations: A Direct Demonstration in Cell Culture

Cited by 945 publications

References 33 publications

Effects of angiotensin II on insulin receptor binding and mRNA levels in normal and diabetic rats

Effects of angiotensin II on insulin receptor binding and mRNA levels in normal and diabetic rats

Muscle insulin receptor concentrations in obese patients post bariatric surgery: relationship to hyperinsulinemia

Human adipose tissue in culture V. Studies on the metabolic effects of insulin

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